A phase 2 trial of IO102-IO103 and nivolumab-relatlimab fixed-dose combination in previously untreated, unresectable melanoma.

TPS9605 Background: One emerging strategy to augment immune checkpoint inhibitor efficacy is to eliminate immunosuppressive cell populations in the tumor microenvironment (TME) through vaccination. IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the TME. IO102-IO103 treatment promotes inflammation and potentiates anti-tumor activity via activation and expansion of T cells against IDO1 and/or PD-L1 positive cells. IO102-IO103 plus nivolumab demonstrated an impressive objective response rate (ORR) of 80% in the phase 1/2 MM1636 trial of 30 patients with previously untreated, unresectable melanoma, and a randomized phase 3 trial of pembrolizumab with or without IO102-IO103 (NCT05155254) is ongoing. No prior studies have evaluated IO102-IO103 in combination with dual PD-1 and LAG-3 blockade with nivolumab-relatlimab (nivo-rela), and to our knowledge there are no existing clinical data for other investigational agents in combination with nivo-rela. Methods: NCT05912244 is a single-arm, investigator-initiated trial testing IO102-IO103 in combination with nivo-rela in patients with previously untreated, unresectable melanoma. Twelve of forty-three planned patients have been enrolled. All patients will be treated with nivo-rela every four weeks for up to two years. IO102-IO103 will be administered subcutaneously every two weeks for the initial eight weeks, and then every four weeks for up to two years. An interim efficacy analysis for futility will be performed after response data are available for 21 patients. Eligible patients must have histologically confirmed, unresectable stage III or stage IV non-uveal melanoma, measurable disease by RECIST v1.1, an ECOG performance status of 0 or 1, and definitive treatment of any brain metastases. Prior systemic treatment in the neoadjuvant or adjuvant setting is allowed if completed at least six months prior to trial enrollment. Available pre-treatment melanoma tissue is required, and all patients will undergo an on-treatment study biopsy between the second and third dose of nivo-rela. Peripheral blood mononuclear cells will be collected prior to the first three doses of nivo-rela. The primary endpoint is ORR by RECIST v1.1, weighted by PD-L1 expression. Secondary endpoints include safety assessed by Common Terminology Criteria for Adverse Events v 5.0 , progression-free survival (PFS) by RECIST v1.1, duration of disease response, and disease control rate. Exploratory correlative endpoints include assessment of changes in PD-L1 and IDO-expressing cells in the TME on paired tumor biopsies, identification of peripheral PD-L1 and IDO-reactive cells in the peripheral blood by ELISpot, and assessment of peripheral pre-treatment and on-treatment T cell clonality by TCR sequencing. Clinical trial information: NCT05912244 .